In China, with the acceleration of the aging process of the society, the number of patients suffering from cardiovascular diseases has increased rapidly. This type of diseases has long disease courses, high cost, and high mortality rate and disability rate. As the incidence of the cardiovascular diseases caused by vascular embolism has increased year by year, the cardiovascular diseases have become a major public health problem in China.
Studies have shown that platelet overactivation plays an important role in the development and progression of thrombosis and thrombotic diseases. Therefore, inhibiting excessive activation of platelets and reducing adhesion, aggregation and release of the platelets are important means for preventing and treating the thrombotic diseases. At present, anti-platelet medicaments clinically used for preventing and treating the thrombotic diseases are mainly divided into three categories, the first category is the medicaments affecting platelet metabolism enzymes, such as cyclooxygenase inhibitors, thromboxane A2 (TXA2) inhibitors, phosphodiesterase (PDE) inhibitors and the like; the second category is adenosine diphosphate (ADP) inhibitors, such as ticlopidine, clopidogrel, ticagrelor and the like, which inhibit the aggregation of the platelets by inhibiting P2Y12 receptors of the platelets; and the third category is platelet GP IIb/IIIa receptor antagonists, such as abciximab and eptifibatide, which inhibit the aggregation of the platelets by competitively blocking binding of fibrinogen with GP IIb/IIIa receptors on the surfaces of the platelets. Most of the above traditional anti-platelet medicaments resist thrombosis by inhibiting TXA2 or ADP. However, because both TXA2 and ADP participate in the normal hemostasis process and play an important role in the process, TXA2 or ADP inhibitors also affect the normal hemostatic function of a human body while blocking the pathological thrombosis process, thereby increasing the probability and risk of bleeding in the patient.
Protease-activated receptor-1 (PAR) is a member of a G-protein coupled receptor family. Humans have four receptor subtypes, namely PAR1, PAR2, PAR3 and PAR4. However, only PAR1 and PAR4 are distributed on the surfaces of the platelets. PAR1 plays a more important role in the thrombin-mediated platelet activation process. Thrombin can activate PAR1 at a relatively low concentration and further activate the platelets, resulting in rapid aggregation of the platelets. Inhibition of the PAR1 receptor can block the thrombin-mediated platelet aggregation and pathological thrombus expansion process without affecting the normal protective hemostasis process of the human body, in which TXA2 and ADP participate. Thus, PAR1 is an ideal anti-platelet medicament target.
Vorapaxar Sulfate is a PAR1 inhibitor which is first created by Merck Sharp & Dohme Ltd, and was approved by FDA for marketing in May 2014. The medicament is used for the patients suffering from heart attacks or the patients with blocked arteries in legs, and can further reduce the risk of the heart attacks and strokes. As the Vorapaxar blocks the platelet aggregation by inhibiting PAR1, the medicament does not affect the normal hemostasis process and can reduce the risk of accidental bleeding in the patient. Although the Vorapaxar has good anti-coagulation activity, it has the disadvantages of a complicated structure (having 7 chiral centers), a long synthetic route (16 linear synthesis steps) and high preparation cost.
Natural products are important sources for research and development of novel medicaments due to the characteristics of various kinds, complicated structure, clear chirality, fixed conformation and the like. The cheap and readily available natural products are used as starting raw materials or precursors of the medicaments to perform structural transformation and modification, so that rapid construction and large-scale preparation of the medicaments can be achieved, and the production cost can be also effectively reduced. Andrographolide, which is a diterpenoid compound, and polygodial, which is a sesquiterpenoid compound, are common important active natural products, and their structural formulas are as follows:

The conformation of the chiral center in each structure is identical to the corresponding conformation of the key chiral center in the structure of Vorapaxar. Therefore, under the premise of ensuring that the conformation of the key chiral center remains unchanged, using the diterpenoid compound and the sesquiterpenoid compound as the precursors to perform structural modification and transformation is an important way to rapidly discover novel PAR1 inhibitor type medicaments.